Angiomyogenesis for myocardial repair

Abstract

The conventional therapeutic modalities for myocardial infarction have limited success in preventing the progression of left ventricular remodeling and congestive heart failure. The heart cell therapy and therapeutic angiogenesis are two promising strategies for the treatment of ischemic heart disease. After extensive assessment of safety and effectiveness in vitro and in experimental animal studies, both of these approaches have accomplished the stage of clinical utility, albeit with limited success due to the inherent limitations and problems of each approach. Neomyogenesis without restoration of regional blood flow may be less meaningful. A combined stem-cell and gene-therapy approach of angiomyogenesis is expected to yield better results as compared with either of the approaches as a monotherapy. The combined therapy approach will help to restore the mechanical contractile function of the weakened myocardium and alleviate ischemic condition by restoration of regional blood flow. In providing an overview of both stem cell therapy and gene therapy, this article is an in-depth and critical appreciation of combined cell and gene therapy approach for myocardial repair.

FIG. 1.

Confocal images of the infarcted rat heart histologic sections 7 days after transplantation of the preconditioned SkMs. The cells were labeled with cell-tracker dye PKH26 (A; red). The tissue sections were immunostained for Ki67 expression, a marker for cell proliferation (B; green). The nuclei were visualized with DAPI staining (C; blue). (D) The merged image. The number of Ki67+ cells (white arrows) was significantly higher in the preconditioned cell-engrafted hearts as compared with the non-preconditioned cell-transplanted hearts (p < 0.001) (original magnification, ×630). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 2.

Confocal images of the rat heart-tissue section at 6 weeks after transplantation of SkMs labeled with PKH26 cell tracker dye (A; red). The histologic sections were immunostained for myosin heavy chain (slow-isoform) expression (B; cyan). The nuclei were visualized with DAPI staining (C; blue). (D) Merged image showing extensive myogenic differentiation of the transplanted cells in the infarcted myocardium (original magnification, × 630). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 3.

Fluorescent photomicrographs of the infarcted rat heart at 6 weeks after engraftment of diazoxide-preconditioned SkMs labeled with PKH26 (red; A). The tissue sections were double immunostained for von Willebrand factor VIII (green; B) and smooth muscle actin (blue; C). (D) Merged image showed extensive angiogenic response; the majority of the blood vessels formed were mature, as indicated by their positivity for smooth muscle actin (magnification, × 400). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 4.

Fluorescent immunostaining of mesenchymal stem cells on day 4 after transduction with adenoviral vectors encoding for (A) Akt (red fluorescence) and (B) angiopoietin-1 (green fluorescence). (C) Merged image showing mesenchymal stem cells simultaneously overexpressing both Akt and angiopoietin-1 (original magnification, × 630). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 4.

Fluorescent immunostaining of mesenchymal stem cells on day 4 after transduction with adenoviral vectors encoding for (A) Akt (red fluorescence) and (B) angiopoietin-1 (green fluorescence). (C) Merged image showing mesenchymal stem cells simultaneously overexpressing both Akt and angiopoietin-1 (original magnification, × 630). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).